Kaposi's sarcoma (KS) was one of the first AIDS-defining illnesses, and continues to be a source of substantial morbidity and mortality. Current therapeutic strategies and regimens for widespread or visceral disease are toxic and have not yielded significant prolongation of survival. Recent advances in the ability to culture KS spindle cells in vitro over the past several years have begun to lay the foundation for the consideration of novel approaches to the therapy of KS. In particular, evidence has emerged that a cascade of cytokines and other growth factors are important in the development of KS lesions. In addition, there is evidence that angiogenesis is important in this process. In the Retroviral Diseases Section, we have initiated a pre-clinical and clinical program to develop therapies for KS. Using the methodology initially developed by Dr. Gallo's laboratory, we have developed several spindle cell lines from patients with KS which grow in response to retroviral-conditioned media. We are now in the process of characterizing those lines. One important question to be addressed is whether these lines are unique to KS per se, or whether they are normal cells stimulated by cytokines. In preliminary experiments, we have learned that these lines are inhibited by pentosan polysulfate and by TNP-470 (an angiogenesis inhibitor initially developed by Dr. J. Folkman and Takada Co.) We will continue to study these and other in vitro models for KS and to use them to develop therapeutic strategies. We have recently completed a pilot study of pentosan polysulfate in patients with KS, and are in the process of initiating trials of all-trans retinoic acid (RA) (alone and in combination with alpha-interferon) and of TNP-470.